Formulations and methods for vaginal delivery of antiprogestins

ABSTRACT

The subject matter of the present invention is pertinent to the field of vaginal delivery of pharmaceutically active agents. Embodiments of the instant invention disclose methods for treating a variety of progesterone related disorders by vaginal administration of a pullulan capsule and a fill formulation comprising one or more antiprogestins dispersed in a mixture of isopropyl palmitate or isopropyl myristate and a polyethylene glycol.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/988,766 filed May 5, 2014, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

In several embodiments, the present invention relates to mucoadhesivepharmaceutical compositions and their use for local administration ofactive agents such as antiprogestins to the vaginal mucosa. In relatedembodiments, the mucoadhesive compositions are administered for thetreatment of a variety of progesterone related conditions.

BACKGROUND OF THE INVENTION

The effect of the steroid hormone progesterone on the reproductivesystem has been well-documented. For example, progesterone is vital toestablishing and maintaining pregnancy and exerts actions on varioustissues of the reproductive system. The action of progesterone ontissues outside the reproductive system has been reported but is lesswell characterized.

Antiprogestins, compounds which inhibit the action of progesterone, haveconsiderable potential for use in the pharmacological regulation offertility and a variety of conditions and diseases such as breast cancerand endometriosis. The first reported antiprogestin, mifepristone (RU486), is one of a number of 19-nortestsosterone derivatives with strongaffinity for both the progesterone and glucocorticoid receptors and withantiprogestational and antiglucocorticoid activity. A variety ofantiprogestins based on the 19-norprogesterone backbone have also beensynthesized.

Several drawbacks are associated with the use of known antiprogestins,rendering them less than ideal for chronic administration, particularlywhen delivered orally. If these and other limitations associated withantiprogestin treatment could be improved, a significant advance in thetreatment of hormone-dependent disorders would result.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a mucoadhesive capsulecomprising pullulan and a capsule fill formulation comprising an activeagent, preferably an antiprogestin and one or more excipients fordelivering the active agent to the vaginal mucosa.

In other embodiments, the present invention provides methods for thetreatment of a variety of progesterone related conditions in a patientin need of such treatment by administering a mucoadhesive capsulecomprising pullulan and a capsule fill formulation comprising anantiprogestin and one or more excipients to the vaginal mucosa of thepatient.

In other embodiments, the present invention provides a kit comprising amucoadhesive capsule comprising pullulan and a capsule fill formulationcomprising an active agent, preferably an anitprogestin and one or moreexcipients for delivering the agent to the vaginal mucosa in combinationwith an vaginal applicator.

Progesterone-related conditions that may be treated with themucoadhesive capsules of the invention include, without limitation,endometriosis and pain associated therewith, adenomyosis, endometriomasof the ovary, dysmenorrhea, endocrine hormone-dependent tumors, uterinefibroids, endometrial hyperproliferation, ovarian cancer, cervicalcancer and breast cancer. Compositions of the instant invention may alsobe used to induce menses, to induce labor and for contraception.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the area under the curve (AUC) of CDB-4124 and itsmonodemethylated metabolite CDB-4453, following administration ofCDB-4124 to human females with uterine fibroids at 1 mg, 3 mg, 6 mg, 9mg and 12 mg oral doses compared with vaginal administration of a 12 mgdose.

FIG. 2 illustrates a comparison of the Cmax (peak serum concentration)of CDB-4124 and CDB-4453 following 1 mg, 3 mg, 6 mg, 9 mg, and 12 mgoral doses to human females with uterine fibroids compared with vaginaladministration of a 12 mg dose.

FIG. 3 illustrates pharmacokinetic data observed at steady state over a24 hour period following administration of 1 mg, 3 mg, 6 mg, 9 mg and 12mg oral versus 12 mg vaginal doses of CDB-4124.

FIG. 4A-B illustrates pharmacokinetic data observed over a 24 hourperiod in rabbits following the last of 10 daily doses of 12 mg CDB-4124delivered vaginally. Panel A illustrates CDB-4124; Panel B illustratesCDB-4453.

FIG. 5 illustrates the applicator used to vaginally deliver pullulancapsules comprising 12 mg CDB-4124 to human females.

FIGS. 6-13 illustrate total pharmacokinetic data (CDB-4124+CDB-4453)observed over a 32 hour period in healthy human females following asingle vaginal dose of pullulan capsules comprising 12 mgCDB-4124+99.98% PEG 1000+0.02% BHT (A) or a single vaginal dose ofpullulan capsules comprising 12 mg CDB-4124+95.98% PEG 1000+4% isopropylmyristate+0.02% BHT (B1) or following 7 daily vaginal doses of pullulancapsules comprising 12 mg CDB-4124+95.98% PEG 1000+4% isopropylmyristate+0.02% BHT (B2).

DETAILED DESCRIPTION OF THE INVENTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any way. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

It is to be understood that any ranges, ratios and ranges of ratios thatcan be formed by any of the numbers or data present herein representfurther embodiments of the present invention. This includes ranges thatcan be formed that do or do not include a finite upper and/or lowerboundary. Accordingly, the skilled person will appreciate that many suchratios, ranges and ranges of ratios can be unambiguously derived formthe data and numbers presented herein and all represent embodiments ofthe invention.

Before the present compounds, compositions and methods are disclosed anddescribed, it is to be understood that the terminology used herein isfor the purpose of describing particular embodiments only and is notintended to be limiting. It must be noted that, as used in the presentspecification and the appended claims, the singular forms “a,” “an” and“the” include plural referents unless the context clearly dictatesotherwise.

Definitions

The term “capsule” refers to a hard shell pharmaceutical capsule. Thecapsule consists of a body and cap and may comprise a fill formulationcontaining a pharmacologically active agent.

The term “oral” administration means that the active agent is in aformulation designed to be ingested, i.e. designed to be delivered tothe gastrointestinal system for absorption.

The term “effective dosage” means an amount of the composition's activecomponent sufficient to treat a particular condition.

The term “selective progesterone receptor modulators” means compoundsthat affect functions of progesterone receptor in a tissue-specificmanner. The compounds act as progesterone receptor antagonists in sometissues (for example, in breast tissue) and as progesterone receptoragonists in other tissues (for example, in the uterus).

The term “treat” or “treatment” as used herein refers to any treatmentof any progesterone-dependent disorder or disease, and includes, but isnot limited to, inhibiting the disorder or disease arresting thedevelopment of the disorder or disease; relieving the disorder ordisease, for example, causing regression of the disorder or disease; orrelieving the condition caused by the disease or disorder, relieving thesymptoms of the disease or disorder.

The term “prevent” or “prevention,” in relation to aprogesterone-dependent disorder or disease, means preventing the onsetof disorder or disease development if none had occurred, or preventingfurther disorder or disease development if the disorder or disease wasalready present. For example, compositions of the present invention maybe used to prevent the recurrence of tumors. Recurrence of tumors mayoccur because of residual microscopic groups or nests of tumor cellswhich subsequently expand into clinically detectable tumors.

The term “progesterone agonist” means a compound that binds to aprogesterone receptor and mimics the action of the natural hormone.

The term “progesterone antagonist” means a compound that binds to aprogesterone receptor and inhibits the effect of progesterone.

In several embodiments, the present invention relates to methods ofadministering an active agent to the vaginal mucosa utilizing a capsulecomprising pullulan and a capsule fill formulation comprising the activeagent and one or more excipients.

In preferred embodiments, the present invention relates to methods oftreating a progesterone related condition by vaginal administration of amucoadhesive capsule comprising pullulan and a capsule fill formulationcomprising an antiprogestin and one or more excipients to the vaginalmucosa of the patient.

Pullulan is a linear, water soluble polysaccharide polymer consisting ofmaltotriose units connected to each other by an α-1,6 glycosidic bond.The three glucose units in each maltotriose unit are connected by anα-1,4 glycosidic bond. The linkage pattern of pullulan is responsiblefor the adhesive properties of the polysaccharide and its capacity forforming fibers and oxygen-impermeable films. Pullulan is produced fromstarch by the fungus Aureobasidium pullulans and can be producedcommercially by batch fermentation as described in Leathers, Appl.Microbiol. Biotechol., 62:468-473 (2003).

Capsules

Capsules suitable for use according to the invention include, withoutlimitation NPcaps® available from Capsugel which contain pullulan,carageenan and potassium chloride, as well as capsules described in U.S.Pat. No. 8,105,625 and US Patent Application Publication No.2005/0249676, the contents of each of which are incorporated herein byreference.

In one aspect, capsules for use according to the invention comprisepullulan with a molecular weight between about 50 to 500 kDa, between100 to 400 kDa, between about 150 to 300 kDa and preferably betweenabout 180 and 250 kDa.

In another aspect, capsules for use according to the invention comprisepullulan from about 50% to about 100% by weight (unfilled capsule). Inother aspects, the capsules comprise about 60 to 90 or 70 to 90, or 80to 90 wt % pullulan. Preferably the capsules comprise about 85 to 90 wt% pullulan.

Capsules for use according to the invention may further comprise (inaddition to pullulan), without limitation, one or more gelling agents(e.g. hydrocolloids or polysaccharides such as alginates, agar gum, guargum, carob, carrageenan, tara gum, gum arabic, pectin, xanthan and thelike); salts comprising cations such as K⁺, Li⁺, Na⁺, NH4⁺, Ca²⁺, Mg²⁺;and/or surfactants such as sodium lauryl sulphate, dioctyl sodiumsulfosuccinate, benzalkonium chloride, benzethonium chloride, cetrimide,fatty acid sugar esters, glycerl monooleate, polyoxyethylene sorbitanfatty acid esters, polyvinylalcohol, dimethylpolysiloxan, sorbitanesters or lecithin, as described in US Patent Application PublicationNo. 2005/0249676.

Capsules for use according to the invention may further comprise one ormore plasticizing agents (e.g. glycerol, propylene glycol, polyvinylalcohol, sorbitol, maltitol and the like); dissolution enhancing agents(e.g. maltose, lactose, sorbitol, mannitol, xylitol, maltitol and thelike); strengthening agents (e.g. polydextrose, cellulose, maltodextrin,gelatin, gums and the like); colorants, and/or opacifiers as describedin U.S. Pat. No. 8,105,625.

In a preferred embodiment, the capsule comprises pullulan in an amountof 85% to 90% by weight, potassium chloride in an amount of 1.0% to 1.5%by weight, carrageenan in an amount of 0.1% to 0.4% by weight, one ormore surfactants in an amount of 0.1% to 0.2% by weight and water in anamount of 10% to 15% by weight.

In a particularly preferred embodiment, the capsule comprises pullulanin an amount of 86.3% by weight, potassium chloride in an amount of1.32% by weight, carrageenan in an amount of 0.27% by weight,surfactants selected from sugar esters, sorbitan monolaurate andcombinations thereof in an amount of 0.15% by weight and water in anamount of 12% by weight.

In another aspect, the pullulan capsule provides a continual release ofthe active agent at a substantially constant rate over a period of time(i.e. a steady release of the active agent) to the subject. The presentinventors have discovered that capsules comprising pullulan aresurprisingly advantageous for vaginal delivery of active agents. Inparticular, pullulan-based capsules are a safe, effective and convenientvehicle for delivering active agents to the vaginal mucosa. The presentinventors have discovered that pullulan capsules adhere to the vaginalmucosa, ensuring that the capsules remain the in vagina at a desiredlocation for the duration of drug delivery. Moreover, due in part to thesolubility of pullulan, no residual capsule is left in the vagina afterrelease of the drug, unlike conventional gelatin capsules. The presentinventors surprisingly discovered that, when used as a vaginal deliverydevice, pullulan capsules effect a continual release of active agents ata substantially constant rate maintaining a low Cmax (peakconcentration) of the active agent and ensuring a high localconcentration of the drug. Thus, sustained levels of the active agentare delivered to the vaginal mucosa while systemic concentrations areminimized.

The capsule fill formulation may comprise any active agent. Preferably,the capsule fill formulation comprises an antiprogestin which may be apure antiprogestin or a selective progesterone receptor modulator.

The capsule fill formulation may further contain one or more excipients.Appropriate excipients can be selected based on considerations includingwithout limitation the active agent to be administered and the dosage.Excipients can function as bulking agents, release modifiers, wettingagents, tonicity agents or combinations thereof. For example, excipientsmay include hydrophilic excipients such as water soluble synthetic andnatural polymers including without limitation polyethylene glycol (PEG),polyvinyl pyyrolidone, polymethacrylates, polylysine, polyvinyl alcohol,albumin, alginate, gelatin, chitosan, cellulose, ficoll, starchy,hydroxyethyl cellulose, hydroxypropyl cellulose, hyaluronic acid,carboxyethyl cellulose, carboxymethyl cellulose, dextran sulfate andderivatives thereof. Particular hydrophilic polymers for use in capsulefill formulations may be based on factors such as molecular weight,hydrophilicity and visocity. Hydrophilic polymers may be used as bulkingor wetting agents.

Excipients may also include lipids such as, without limitation, one or amixture of different grades of Gelucire, Labrafil®, Labrasol® and thelike. Gelcuire compositions are amphiphilic inert polygycolizedglycerides which form micelles in aqueous media. They are identified bytheir melting point (degrees Celsius)/HLB (hydrophile-lipophile kalance)value. Particularly preferred Gelucire compositions for use in thecapsules are Gelucire 44/14 (lauroyl polyoxyl-32 glycerides) andGelucire 50/13 (stearoyl polyoxyl-32 glycerides).

In a preferred embodiment, the fill formulation comprises apharmaceutically active compound, preferably CDB-4124, and excipientsGelucire 44/14 and PEG. In related aspects, Gelucire 44/14 is present asbetween 50% and 90%, preferably about 75% excipient w/w and PEG ispresent as between 50% and 10%, preferably about 25% excipient w/w. Inparticularly preferred embodiment, the fill formulation comprisesCDB-4124 and excipients consisting of 74.13% (w/w) Gelucire and 25.87%PEG 400.

In particularly preferred embodiments, the capsule fill formulationconsists of or consists essentially of a pharmaceutically active agent,preferably CDB-4124, and about 100% w/w PEG 1000 as excipient.Optionally, 0.02% butylated hydroxytoluene is also present at 0.02%excipient w/w (as antioxidant).

In other preferred embodiments, the capsule fill formulation comprises apharmaceutically active agent, preferably CDB-4124, and excipientscomprising 30% to 60% w/w Wecobee M (fatty acid ester), 30% to 60% w/wPEG 1000 and 0.1% to 5% w/w lecithin. In a related embodiment, thecapsule fill formulation comprises CDB-4124 as active agent andexcipients consisting of about 50% (e.g. 50.1%) w/w Wecobee M, about 50%(e.g. 49.4%) w/w PEG 1000 and about 0.5% w/w lecithin.

It has surprisingly been found that dispersing an active ingredient suchas CDB-4124 in a mixture of isopropyl myristate or isopropyl palmitatewith a polyethylene glycol, increases the AUC of the active ingredientwithout significantly altering the C_(max). Therefore, capsules havingsuch fill formulation allow an increase in bioavailability compared withfill formulations lacking isopropyl myristate or isopropyl palmitatewithout a corresponding increase in peak concentration of the activeagent.

In preferred embodiments, the capsule fill formulation comprises apharmaceutically active agent, preferably CDB-4124, dispersed in amixture of isopropyl myristate with a polyethylene glycol or a mixtureof isopropyl palmitate with a polyethylene glycol. The isopropylmyristate or isopropyl palmitate comprises about 15% to about 1%excipient w/w and PEG comprises about 85% to about 99% excipient w/w.For example, isopropyl myristate or isopropyl palmitate may compriseabout 10% to about 2% excipient w/w, from about 6% to about 3% excipientw/w, from about 5% to about 4% excipient w/w or any other range withinabout 15% to about 1%. In other embodiments, the w/w ratio betweenpolyethylene glycol and isopropyl myristate or isopropyl palmitate inthe fill formulation is in the range of 99:1 to 5.7:1.

In a particularly preferred embodiment, the capsule fill formulationcomprises CDB-4124, dispersed in a mixture of isopropyl myristate andPEG 1000, wherein isopropyl myristate is present at about 4% excipientw/w and PEG 1000 is present at about 96% w/w. Optionally, 0.02%butylated hydroxytoluene is also present at 0.02% excipient w/w (asantioxidant).

In related embodiments, the capsule fill formulation comprises apharmaceutically active agent, preferably CDB-4124, a transdermalpermeation enhancer selected from dimethyl sulfoxide (DMSO),mono-unsaturated fatty acids (e.g. oleic acid), poly-unsaturated fattyacids (e.g. linoleic acid), ethanol, 1-dode-cylazacycloheptan-2-one, andmineral oil and optionally a polyethylene glycol. Preferably, thepermeation enhancer comprises about 99% to about 1% excipient. Morepreferably, the capsule fill formulation comprises a transdermalpermeation enhancer and PEG wherein the permeation enhancer comprisesabout 15% to about 1% excipient w/w and PEG comprises about 85% to about99% excipient w/w. For example, permeation enhancer may comprise about10% to about 2% excipient w/w, from about 6% to about 3% excipient w/w,from about 5% to about 4% excipient w/w or any other range within about15% to about 1%. In other embodiments, the w/w ratio betweenpolyethylene glycol and permeation enhancer in the fill formulation isin the range of 99:1 to 5.7:1.

Excipients may also include sugars such as mannitol, sorbitol, xylitol,glucitol, ducitol, inositol, arabinitol, arabitol, galactitol, iditol,allitol, fructose, sorbose, glucose, xylose, trehalose, dextrose,galactose, talose, ribose, arabinose, sucrose, maltose, lactose, fucose,matotriose, and the like. The amount of sugar may be adjusted to provideosmolality or wetting.

Wetting agents can be used in the capsule fill drug formulation tofacilitate water ingress into the capsule and wetting of the activeagent and include gelatin, casein, lecithin, gum acacia, cholesterol,calcium stearate, stearic acid, etc.

The capsule fill formulation may further comprise one or moredisintegrants such as corn starch, potato starch, modified starches,microcrystalline cellulose, methyl cellulose, carboxymethylcelullose,sodium alginate, cellulose polyacrilin potassium, gums, agar, guar,locust bean, pectin, xanthan, agar, etc.

The capsule fill formulation may comprise one or more flow agents, orglidants to promote flowability including colloidal silica, cornstarch,talc, calcium silicate, magnesium silicate, tribasic calcium phosphate,silicon hydrogel, etc.

The capsule fill formulation may further comprise a foaming agent suchas polyethylene glycol, saponin, sorbitan trioleate, sorbitanmonostearate, sorbitan monopalmitate, glyceryl monostearate, and thelike.

Active Agents

The capsule fill formulation may comprise any pharmacologically activeagent which has a therapeutic effect when delivered vaginally.

In some embodiments, the capsule fill formulation comprises an estrogen(i.e. a natural estrogen or a synthetic compound that mimics thephysiological effect of natural estrogens) including, withoutlimitation, estradiol (17β-estradiol), estridiol acetate, estradiolbenzoate, estridiol cypionate, estridiol decanoate, estradiol diacetate,estradiol heptanoate, estradiol valerate, 17α-estradiol, estriol,estriol succinate, estrone, estrone acetate, estrone sulfate,estropipate (piperazine estrone sulfate), ethynylestradiol(17α-ethynylestradiol, ethinylestradiol, ethinyl estradiol, ethynylestradiol), ethynylestradiol 3-acetate, ethynylestradiol 3-benzoate,mestranol, quinestrol, nitrated estrogen derivatives or combinationsthereof.

In other embodiments, the capsule fill formulation comprises a progestin(i.e. natural or synthetic compounds that possesses progestationalactivity including, without limitation,17α-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one,17α-ethynyl-19-nortestosterone, 17α-ethynyltestosterone,17-deacetylnorgestimate, 19-nor-17-hydroxyprogesterone,19-norprogesterone, 3β-hydroxydesogestrel, 3-ketodesogestrel(etonogestrel), acetoxypregnenolone, algestone acetophenide,allylestrenol, amgestone, anagestone acetate, chlormadinone,chlormadinone acetate, cyproterone, cyproterone acetate,d-17β-acetoxy-13β-ethyl-17α-ethynylgon-4-en-3-one oxime, demegestone,desogestrel, dienogest, dihydrogesterone, dimethisterone, drospirenone,dydrogesterone, ethisterone (pregneninolone, 17α-ethynyltestosterone),ethynodiol diacetate, fluorogestone acetate, gastrinone, gestadene,gestodene, gestonorone, gestrinone, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, hydroxyprogesterone,hydroxyprogesterone acetate, hydroxyprogesterone caproate,levonorgestrel (1-norgestrol), lynestrenol (lynoestrenol),mecirogestone, medrogestone, medroxyprogesterone, medroxyprogesteroneacetate, megestrol, megestrol acetate, melengestrol, melengestrolacetate, nestorone, nomegestrol, norelgestromin, norethindrone(norethisterone) (19-nor-17α-ethynyltestosterone), norethindrone acetate(norethisterone acetate), norethynodrel, norgestimate, norgestrel(d-norgestrel and dl-norgestrel), norgestrienone, normethisterone,progesterone, promegestone, quingestanol, tibolone, trimegestone, orcombinations thereof.

In other embodiments, the capsule fill formulation comprises a progestinand an estrogen.

In a preferred embodiment, the active agent is a progesteroneantagonist.

In one embodiment, the capsule fill formulation comprises a steroidcompound disclosed in U.S. Pat. Nos. 6,861,415 and 6,900,193, thecontents of which are incorporated herein by reference. In a preferredembodiment, the steroid compound is CDB-4124(21-methoxy-17α-acetoxy-11β-(4 N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) or CDB-4453(21-methoxy-17α-acetoxy-11β-(4-N-methylaminophenyl)-19-norpregna-4,9-diene-3,20-dione).

Other preferred progesterone antagonists that may be present in thecapsule fill formulation include, without limitation, Mifepristone(RU-486; 11β-[4N,N-dimethylaminophenyl]-17β-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one),Lilopristone (11β-(4N,N-dimethylaminophenyl)-17β-hydroxy-17-((Z)-3-hydroxypropenyl)estra-4,9-dien-3-one),Onapristone (11β-(4N,N-dimethylaminophenyl)-17α-hydroxy-17-(3-hydroxypropyl)-13α-estra-4,9-dien-3-one),asoprisnil (benzaldehyde,4-[(11β,17β)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4,9-dien-11-yl]-1-(E)-oxim;J867), its metabolite J912(4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyd-(1E)-oxim)and CDB-2914(17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-dien-3,20-dione).

Other antiprogestins that may be present in the capsule fill formulationinclude compounds described in U.S. Pat. Nos. 4,386,085, 4,447,424,4,536,401, 4,519,946, 4,609,651, 4,634,695, 4,780,461, 4,814,327,4,829,060, 4,871,724, 4,921,845, 4,921,845, 5,095,129, 5,446,178,5,478,956, 5,232,915 5,089,488, 5,093,507, 5,244,886, 5,292,878,5,439,913, 5,446,036, 5,576,310; 5,684,151, 5,688,808, 5,693,646,5,693,647, 5,696,127, 5,696,130, 5,696,133 5,739,125, 5,407,928,5,273,971, 5,728,689, 5,753,655, 5,843,933, 5,843,931, 6,509,334,6,566,358, 6,713,478, 6,391,907, 6,417,214, 6,380,235, 6,339,098,6,306,851, 6,441,019, 6,369,056, and 6,358,948, the contents of each ofwhich are incorporated herein by reference.

Other antiprogestins that may be useful in the invention include,without limitation JNJ-1250132,(6α,11β,17β)-11-(4-dimethylaminophenyl)-6-methyl-4′,5′-dihydrospiro[estra-4,9-diene-17,2′(3′H)-furan]-3-one(ORO-31710);(11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one(ORG-33628);(7β,11β,17β)-11-(4-dimethylaminophenyl-7-methyl]-4′,5′-dihydrospiro[estra-4,9-diene-17,2′(3′H)-furan]-3-one(ORG-31806); ZK-112993; ORG-31376; ORG-33245; ORG-31167; ORG-31343;RU-2992; RU-1479; RU-25056; RU-49295; RU-46556; RU-26819; LG1127;LG120753; LG120830; LG1447; LG121046; CGP-19984A; RTI-3021-012;RTI-3021-022; RTI-3021-020; RWJ-25333; ZK-136796; ZK-114043; ZK-230211;ZK-136798; ZK-98229; ZK-98734; ZK-137316;4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-oxime;4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-[O-(ethylamino)carbonyl]oxime;4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-[O-(ethylthio)carbonyl]oxime;(Z)-6′-(4-cyanophenyl)-9,11α-dihydro-17β-hydroxy-17α-[4-(1-oxo-3-methylbutoxy)-1-butenyl]4′H-naphtho[3′,2′,1′;10,9,11]estr-4-en-3-one;11β-(4-acetylphenyl)-17-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;11beta-(4-Acetylphenyl)-19,24-dinor-17,23-epoxy-17alpha-chola-4,9,20-trien-3-one;(Z)-11beta,19-[4-(3-Pyridinyl)-o-phenylene]-17beta-hydroxy-17α-[3-hydroxy-1-propenyl]-4-androsten-3-one;11beta-[4-(1-methylethenyl)phenyl]-17α-hydroxy-17beta-(3-hydroxypropyl)-13α-estra-4,9-dien-3-one;4′,5′-Dihydro-1beta-[4-(dimethylamino)phenyl]-6beta-methylspiro[estra-4,9-dien-17beta,2′(3′H)-furan]-3-one.

In related aspects, capsule fill formulations comprise apharmaceutically acceptable salt of a pharmaceutically active compoundsuch as an antiprogestin. Depending on the process conditions the saltcompound obtained may be either in neutral or salt form. Salt formsinclude hydrates and other solvates and also crystalline polymorphs.Both the free base and the salts of these end products may be used inaccordance with the invention. Acid addition salts may in a manner knownper se be transformed into the free base using basic agents such asalkali or by ion exchange. The free base obtained may also form saltswith organic or inorganic acids.

In the preparation of acid addition salts, preferably such acids areused which form suitably pharmaceutically acceptable salts. Examples ofsuch acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitricacid, aliphatic acid, alicyclic carboxylic or sulfonic acids, such asformic acid, acetic acid, propionic acid, succinic acid, glycolic acid,lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,glucuronic acid, fumaric acid, maleic acid, hydroxymaleic acid, pyruvicacid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, embonic acid,ethanesulfonic acid, hydroxyethanesulfonic acid, phenylacetic acid,mandelic acid, alogenbensenesulfonic acid, toluenesulfonic acid,galactaric acid, galacturonic acid or naphthalenesulfonic acid. Allcrystalline form polymorphs may be used in accordance with theinvention.

Base addition salts may also be used in accordance with the inventionand may be prepared by contacting the free acid form with a sufficientamount of the desired base to produce the salt in the conventionalmanner. The free acid form may be regenerated by contacting the saltform with an acid and isolating the free acid in the conventionalmanner. Pharmaceutically acceptable base addition salts are formed withmetals or amines, such as alkali and alkali earth metals or organicamines. Examples of metals used as cations are sodium, potassium,calcium, magnesium and the like. Examples of suitable amines are aminoacids such as lysine, choline, diethanolamine, ethylenediamine,N-methylglucamine and the like.

Disorders that May be Treated by Vaginal Delivery of Pullulan Capsules

Pullulan capsules comprising a fill formulation comprising apharmaceutically active agent may be administered to the vagina of asubject to treat a variety of disorders or achieve a variety of desiredtherapeutic results in a subject. Preferably the subject is a femalemammal, most preferably a human female.

In some embodiments of the invention, a pullulan capsule comprising apharmaceutically active compound is administered to a female patient inneed thereof in order to treat a disorder selected from the groupconsisting of endometrial hyperproliferation, endometriosis (or painassociated therewith), dysmenorrhea, uterine fibroids, adenomyosis,endometrioma, ovarian cancer, cervical cancer. In a preferredembodiment, endometriosis, dysmennorhea, uterine fibroids, adenomyosis,ovarian cancer or cervical cancer is treated by administering anintravaginal preparation containing a compound of general formula I tothe vagina of a patient in need of such treating.

In another embodiment of the invention, a pullulan capsule of theinvention is administered to a female in need thereof in order to inducemenses in the female in which case the capsule fill formulationpreferably comprises a progestin such as medroxyprogesterone 17-acetate.

In yet another embodiment of the invention, a pullulan capsule of theinvention is administered to a female in need thereof in order to inducelabor.

In yet another embodiment of the invention, a pullulan capsule of theinvention is administered to a female in need thereof as acontraceptive, in which case the capsule fill formulation preferablycomprises a progestin and optionally an estrogen.

Dosages and Administration Regimens

A therapeutically effective amount of an active agent required for usein therapy varies with the length of time that activity is desired, andthe age and the condition of the patient to be treated, among otherfactors, and is ultimately determined by the attendant physician. Ingeneral, however, doses employed for human treatment typically are inthe range of about 0.001 mg/kg to about 500 mg/kg per day, for exampleabout 1 μg/kg to about 1 mg/kg per day or about 1 μg/kg to about 100μg/kg per day. For most large mammals, the total daily dosage is fromabout 1 to 100 mg, preferably from about 2 to 80 mg. The dosage regimenmay be adjusted to provide the optimal therapeutic response. The desireddose may be conveniently administered in a single dose, or as multipledoses administered at appropriate intervals, for example as two, three,four or more subdoses per day.

Illustratively, a pullulan capsule of the invention may be vaginallyadministered to a subject to provide the subject with an active agentsuch as an antiprogestin in an amount of about 1 μg/kg to about 1 mg/kgbody weight, for example about 1 μg/kg, about 25 μg/kg, about 50 μg/kg,about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, about 375μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975μg/kg or about 1 mg/kg body weight

Pharmaceutically active compounds are present in the capsule fillformulation at a therapeutically effective dose that is preferably lowercompared to the therapeutically effective dose of the compound whenadministered orally. For example, the therapeutically effective dose maybe less than 50 mg/day, less than 40 mg/day, less than 30 mg/day lessthan 20 mg/day, less than 10 mg/day, less than 5 mg/day, less than 3mg/day, between 1 mg/day and 50 mg/day, between 3 mg/day and 40 mg/day,between 3 mg/day and 30 mg/day, between 3 mg/day and 20 mg/day, between3 mg/day and 10 mg/day, between 5 mg/day and 20 mg/day or between 5 mgand 10 mg/day. In other embodiments, the effective dose may be 3 mg perday to 12 mg/day, 5 mg/day to 12 mg/day, or 12 mg/day to 25 mg/day. Inother embodiments, the effective dose is 1 or 1.5 mg/day, 2 or 2.5mg/day, 3 or 3.5 mg/day, 4 or 4.5 mg/day 5 or 5.5 mg/day, 6 or 6.5mg/day, 7 or 7.5 mg/day, 8 or 8.5 mg/day, 9 or 9.5 mg/day, 10 or 10.5mg/day, 11 or 11.5 mg/day, 12 or 12.5 mg/day, 13 or 13.5 mg/day, 14 or14.5 mg/day, 15 or 15.5 mg/day, 16 or 16.5 mg/day, 17 or 17.5 mg/day, 18or 18.5 mg/day, 19 or 19.5 mg/day, 20 or 20.5 mg/day, 21 or 21.5 mg/day,22 or 22.5 mg/day, 23 or 23.5 mg/day, 24 or 24.5 mg/day or 25 or 25.5mg/day. In another related embodiment, the effective amount of thecompound in the capsule fill formulation is 2-fold, 3-fold, 4-fold5-fold, 6-fold, 7-fold, 8-fold, 9-fold and even 10-fold less than theeffective amount when administered systemically to treat endometriosis,uterine fibroids and other diseases located in that region.

Pullulan capsules comprising a fill formulation comprising an activeagent, as described above, are suitable for prolonged/chronic vaginaladministration because these compounds are expected to exhibit lowsystemic concentrations and therefore little or no liver toxicity. Inone embodiment, the pullulan capsules are administered for anadministration period of least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31 or more days. The capsules may also be administered for anadministration period of least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ormore months. The capsules may also be administered for an administrationperiod of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. Duringthe administration period, the capsules may be administered daily orperiodically such as every other day, every other month, and the likebut are preferably administered once per day. The capsules may also beadministered intermittently. For example, the capsules may beadministered for an administration period of 1, 2, 3, 4, 5 or moremonths, followed by a period of discontinuance, followed by anadministration period of 1, 2, 3, 4, 5 or more months, and so on.

In one embodiment, the capsule is administered intermittently such thatthe subject undergoes menses during at least one discontinuance period.This approach is expected to avoid the adverse effects associated with athickened or stagnant endometrium that may accompany extended treatmentwith progesterone antagonists, such as spotting, breakthrough bleeding,endometrial hyperproliferation or endometrial cancer. At least one, andpreferably every discontinuance period is of sufficient length for thesubject to experience menstruation. More preferably, the subjectexperiences menstruation during every discontinuance period. In aparticularly preferred embodiment, the capsule is administered daily foran administration period of four months, followed by a discontinuanceperiod during which the subject experiences menstruation, followed byanother administration period of four months and so on.

Patients undergoing treatments with the compositions of the instantinvention should be monitored routinely for their serum estrogen andglucocorticoid levels.

The following non-limiting examples are provided to aid in understandingthe teachings of the instant invention.

Example 1. Preparation of Pullulan Capsules Comprising the SelectiveProgesterone Receptor Modulator CDB-4124

The following capsule fill formulations (without active agent) wereliquified at 50-70° C. for liquid fill into capsules or molded intovaginal “tablets” as described below:

Gelucire 44/14 74.13% (excipient w/w) PEG 400 25.87% (excipient w/w)Wecobee M 50.1% (excipient w/w) PEG 1000 49.4% (excipient w/w) Lecithin0.5% (excipient w/w) PEG1000 100% or 99.98% (excipient w/w) Butylatedhydroxytoluene 0% or 0.02% (excipient w/w)

The fill formulations were used to fill several kinds of capsulesincluding regular gelatin capsules, soft-gel capsules, and pullulancapsules (Capsugel NPcaps@) or were molded into uncoated vaginal“tablets” in order to test the suitability of the different types ofcapsules or “tablets” as vaginal delivery vehicles.

First, standard gelatin capsules were filled with the above fillformulations, wrapped with moist paper towels and incubated in an ovenat 38° C. to simulate vaginal conditions. Standard gelatin capsules weredetermined to be unacceptable vaginal delivery vehicles in part due tothe length of time necessary for the capsules to soften and release thedrug. Moreover, residual capsule shells will remain in the vagina andneed to be washed out after administration of drug. In addition to theseshortcomings, it was determined that the pills generally would notadhere to the vaginal mucosa. Accordingly, standard gelatin capsuleswere determined to be unacceptable vaginal delivery vehicles.

Next, the fill formulation was molded into uncoated “tablets” using abullet-shaped plastic mold to compress the fill and an applicator wasused to deliver the drug. The uncoated bullet shaped tablets wereadministered vaginally to human females with uterine fibroids. Thismethod of vaginal administration was determined to be impractical due tohandling concerns (the material would often melt during handing prior toadministration and also because a commercial scale process for fillingthe bullet shaped mold was not available.

Standard soft-gel capsules were also tried, but were found to have thesame problems as the gelatin capsules.

Finally, Capsugel NPcaps® were tested as a potential vaginal deliveryvehicle and were determined to be potentially advantageous as thecapsules dissolved in the uterus after a period of time and adhered tothe vaginal mucosa.

Example 2. Pharmacokinetic Animal Studies of Vaginal Delivery of theSelective Progesterone Receptor Modulator CDB-4124

Pullulan capsules (Capsugel NPcaps®, size 0) comprising CDB-4124 wereadministered once daily for 10 consecutive days intravaginally to 10healthy virgin female New Zealand White rabbits in order to determinethe cumulative vaginal mucous membrane irritancy potential and to obtainplasma samples for pharmacokinetic analysis. Five rabbits were assignedto each of two groups, the first dosed with vehicle control (pullulancapsules with 0.5 ml PEG 1000 fill) introduced into the upper vaginalvault of each rabbit using a syringe applicator (Group 1), the secondwith CDB-4124 (pullulan capsules with 12 mg CDB-4124 in 0.5 ml PEG1000)(Group 2). The external vaginal mucosa of each animal was examinedfor erythema, edema and discharge prior to the initial dose, immediatelyprior to each treatment and prior to sacrifice. All animals wereexamined for gross pathology.

All animals survived to the end of the study. The external vaginalmucosa of all Group 1 animals appeared normal during the study and noabnormal physical signs were noted for any animal during the study. Theexternal vaginal mucosa of 2/5 rabbits showed very slight erythemaand/or edema on 4 occasions and appeared normal otherwise. No grossfindings were noted in the ovaries, uterus, or three sections of thevagina in either group, nor were any histopathological findings observedin either group. The irritation index was considered to be “none”. Thedata confirms that pullulan capsules are a safe delivery vehicle foradministering active agents and can be safely used for local vaginaldelivery of CDB-4124 with minimal vaginal irritation.

Samples (0.4 ml blood) for evaluation of pharmacokinetics were collectedfrom each rabbit in Group 2 prior to dosing on the last day (10th dose)and at 1, 2, 3, 4, 6, 7, 10, 16 and 24 hours following the last doseadministration. Average pharmacokinetic data is shown in Table 1 below.A graph depicting data from individual rabbits is illustrated at FIG.4A-B.

TABLE 1 Pharmacokinetic Data (Group II - 5 rabbits) Time (hr) AverageS.D. CDB-4124 0 0.00 0.00 1 79.62 56.32 2 45.22 36.95 3 27.98 23.67 418.69 16.42 6 8.88 12.16 8 5.66 7.75 10 3.94 5.48 16 1.34 2.99 24 0.000.00 AUC 235.06 209.59 Cmax 79.66 56.32 CDB-4453 0 30.88 17.90 1 313.80136.37 2 236.06 119.92 3 175.10 81.51 4 133.88 60.43 6 101.46 49.12 874.10 34.22 10 49.18 21.97 16 38.14 20.99 24 21.98 11.91 AUC 1843.98715.19 CMAX 324.60 141.37

Example 3. Vaginal Administration of Pullulan Capsules ComprisingCDB-4124

Capsugel NPcaps® were filled with the excipient fill formulationsdescribed above with 12 mg CDB-4124 (telapristone acetate) andadministered vaginally to human females with uterine fibroids once perday for a period of 2 weeks to determine the length of time required toreach steady state and overall systemic exposure of the parent compound(CDB-4124) and the primary metabolite (CDB-4453). The capsules wereadministered using a commercially available vaginal applicator modifiedby reversing the insert (see FIG. 5). The unmodified applicatorcomprises a barrel and plunger with the barrel having a relatively wideopening on one end and a relatively narrow opening on the other end. Theapplicator is designed such that the drug is placed in the end with thelarger diameter opening (entrance end), the applicator is inserted intothe vagina and the plunger is used to push the drug out the barrel andinto the vagina. For insertion of the filled NPcaps, the shell end ofthe capsule (having a slightly larger diameter) was placed into thenarrow opening in the barrel, leaving the cap exposed. The NPcaps werefound to adhere to the vaginal mucosa immediately upon insertion, sopatients were advised of the importance of ensuring that the capsule bepositioned properly before capsule release. Pharmacokinetic data wasthen obtained from patients.

Steady state concentration of the drug appeared to be achieved withinone week of administration, after which there was no obvious drug peakas observed in other delivery methods and in contrast to the sameformulation in dogs and rabbits where a drug peak was observed severalhours after delivery. As illustrated at FIG. 1, vaginal administrationof pullulan capsules comprising CDB-4124 resulted in about ⅙th thesystemic exposure of an equivalent oral dose based on area under thecurve (AUC). Cmax on the other hand, as illustrated in FIG. 2, was lowerthan any of the oral doses. As illustrated in FIG. 3, pullulan capsulescomprising CDB-4124 effect a continuous release of active agents at asubstantially constant rate without the high Cmax observed upon oraladministration of the drug.

In a previous oral study, doses of 1, 3, 6, 9 and 12 mg of CDB-4124 wereadministered for a period of 10 weeks. In the oral study, all doses werewell tolerated and reliable cessation of menses was induced at doses aslow as 3 mg. Cessation of menses directly correlates to efficacy of anoral dose in both uterine fibroids and endometriosis. Remarkably avaginal dose of 12 mg, despite achieving only a fraction of the exposureof the ineffective 1 mg oral dose, resulted in cessation of menses in 3of the women. Statistical significance (p<0.05) was seen in a pair-wisecomparison of the 6 women from both the perspective of reduction inmenstrual bleeding using the Pictorial Blood Loss Assessment Chart(PBAC) and also the reduction in overall uterine fibroid symptoms asdetermined by the Uterine Fibroid Symptom Quality of Life Survey(UFSQOL). Given the overall low exposure of the 12 mg dose, in thosewomen that continued to menstruate, further improvements in reduction ofsymptoms are expected with longer exposure to the drug. In efficacystudies in which CDB-4124 was administered orally, women experienced anearly 50% reduction in mean fibroid size at a 25 mg dose. When thosewomen were then escalated to a 50 mg oral dose for an additional fourmonths, fibroid size was reduced to approximately 25% of the initialvolume. Based on the assessment of fibroid symptoms as scored by UFSQOL,women on oral CDB-4124 were, in general, symptom free. It is expectedthat vaginal delivery of CDB-4124 at the 12 mg dose will have greateractivity than the oral 50 mg dose despite a maximum exposure 1/100th ofthe 50 mg oral dose. Even with this low exposure after only 4 weeks oftreatment, significant improvements in fibroid related condition havebeen observed.

Accordingly, administration of pullulan capsules provide a means fordelivering sustained levels of active agent to the vaginal mucosa whileminimizing systemic exposure of the drugs.

Example 4. Vaginal Administration of Pullulan Capsules ComprisingCDB-4124 Dispersed in PEG 1000 and Isopropyl Myristate

A mixture of PEG 1000 (˜96% excipient w/w), isopropyl myristate (˜4%excipient w/w) and BHT (˜0.02% excipient w/w) was heated to 50° C. underconditions of stirring until a clear liquid was obtained. CDB-4124 wasadded and the mixture stirred until CDB-4124 was completely dissolved.After cooling to room temperature under continuous stirring, theformulation was filled into pullulan capsules (Capsugel NPcaps®).

A study was commenced in healthy females to compare the pharmacokinetics(Cmax and AUC) and safety of either 1 or 6 days of dosing with twodifferent formulations of CDB-4124 for vaginal administration. Briefly,volunteers who met the eligibility criteria were randomized to receiveeither the formulation described in Example 3 (12 mg CDB-4124+99.98% PEG1000+0.02% BHT) (Formulation A); or the formulation comprising isopropylmyristate (12 mg CDB-4124+95.98% PEG 1000+4% isopropyl myristate+0.02%BHT) (Formulation B) as their first assigned treatment.

Subjects received either a single dose of Formulation A or daily dosingwith Formulation B for 6 days. After a 7-day washout period subjectsreceived the alternative treatment. On the day of treatment withFormulation A and on the first and last days of treatment withFormulation B subjects remained in the clinic overnight and underwent32-hour pharmacokinetic assessment at the following time points: 0, 0.5,1, 2, 4, 8, 12, 16, 24, 28 and 32 hours after administration of thedrug. Formulation B was administered in the clinic each day after atrough blood sample was drawn.

Tables 2-5 below represent comparisons of AUC and C_(max) offormulations with isopropyl myristate (Formulation B) and withoutisopropyl myristate (Formulation A. Tables 2-4 represent total AUC andC_(max) in subjects after receiving 1 day of dosing with Formulation A(A), 1 day of dosing with Formulation B (B1) or 7 days of dosing withFormulation B (B1). Table 6 represents mean AUC and C_(max) of subjectsreceiving a single dose of Formulation A (A) or Formulation B (B1) or 7days of dosing with Formulation B (B2). The isopropylmyristate-containing formulation surprisingly resulted in a higher areaunder the curve (AUC) but equivalent C_(max) compared to the formulationof Example 3. Addition of isopropyl myristate in the capsule fillformulation resulted in a significant improvement in absorption and asignificant reduction in subject-to-subject variability.

TABLE 2 24-Hour Total AUC (ng-hr/ml) Subject 1 8 10 11 13 18 20 23 MeanSD % CV A 104.8 124.7 35.5 96.6 102.6 97.7 101.8 95 94.84 25.72 27.1 B1166.1 70.8 66.3 150.8 210.2 137.4 85.2 164.9 131.46 52.09 39.6 B2 809.7340.9 201.7 432 794 831.7 648.7 475.9 566.83 238.53 42.1 Ratio: 1.6 0.61.9 1.6 2.0 1.4 0.8 1.7 1.4 B1/A

TABLE 3 32-Hour Total AUC (ng-hr/ml) Subject 1 8 10 11 13 18 20 23 MeanSD % CV A 153.4 169.6 37.9 116.1 139.3 143 144.3 120.1 127.96 40.21 31.4B1 258.7 97.7 97 226.8 294.3 137.4 127 234 184.11 77.93 42.3 B2 1065.9509.9 263.2 558.1 1036.2 1138.2 905.4 652.9 766.23 315.17 41.1 Ratio:1.7 0.6 2.6 2.0 2.1 1.0 0.9 1.9 1.4 B1/A

TABLE 4 32-Hour C_(max) Subject 1 8 10 11 13 18 20 23 Mean SD % CV A 6.66.08 2.26 6.08 6.28 5.94 8.47 5.54 5.91 1.72 29.1 B1 12.37 5.66 4.149.99 11.6 5.55 5.43 9.24 8.00 3.17 39.7 B2 37.34 19.57 9.61 20.17 42.7739.02 33.63 23.76 28.23 11.63 41.2 Ratio: 1.9 0.9 1.8 1.6 1.8 0.9 0.61.7 1.4 B1/A

For Tables 2-4:

A=Formulation A (12 mg CDB-4124+99.98% PEG 1000+0.02% BHT)

B1=Formulation B (12 mg CDB-4124+95.98% PEG 1000+4% isopropylmyristate+0.02% BHT) (1st PK)B2=Formulation B (12 mg CDB-4124+95.98% PEG 1000+4% isopropylmyristate+0.02% BHT) (2nd PK; after daily 12 mg for 7 days)

TABLE 5 AUC (Total; 24 hours) AUC C_(max) (38 Hr) Mean SD Mean SD A**94.84 25.72 5.91 1.72 B1*** 131.46 52.09 8 3.17 B2**** 566.83 238.5328.23 11.63 A** Single Dose (Formulation A) B1*** Day 1 PK (FormulationB) B2**** Daily doses Day 7 PK (Formulation B)

1.-22. (canceled)
 23. A formulation for vaginal use, comprising amucoadhesive capsule comprising pullulan and a capsule fill formulationcomprising a SPRM or a pharmaceutically acceptable salt thereofdispersed in an excipient mixture comprising (a) isopropyl myristate orisopropyl palmitate and (b) a polyethylene glycol, wherein the capsulefill formulation produces an increased AUC with vaginal administrationas compared to a capsule fill formulation lacking isopropyl myristate orisopropyl palmitate.
 24. The formulation of claim 23, wherein theisopropyl myristate or isopropyl palmitate is present in an amountranging from 1% to 15% (w/w) of the excipient mixture and polyethyleneglycol is present in an amount ranging from 99% to 85% (w/w) of theexcipient mixture.
 25. The formulation of claim 24, wherein theisopropyl myristate or isopropyl palmitate is present in an amountranging from 2% to 8% (w/w) of the excipient mixture and polyethyleneglycol is present in an amount ranging from 98% to 92% (w/w) of theexcipient mixture.
 26. The formulation of claim 24, wherein theisopropyl myristate or isopropyl palmitate is present in an amountranging from 3% to 5% (w/w) and polyethylene glycol is present in anamount ranging from 97% to 95% (w/w) of the excipient mixture.
 27. Theformulation of claim 23, wherein the SPRM or the pharmaceuticallyacceptable salt thereof is present in an amount ranging from 2 to 80 mg.28. The formulation of claim 27, wherein the SPRM or thepharmaceutically acceptable salt thereof is present in an amountselected from 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg and 20 mg.29. The formulation of claim 28, wherein the formulation comprises 12 mgof the SPRM or the pharmaceutically acceptable salt thereof.
 30. Theformulation of claim 23, wherein the excipient mixture further comprisesBHT in an amount between 0.01% w/w and 0.03% w/w of the excipientmixture.
 31. The formulation of claim 23, comprising a mucoadhesivecapsule comprising pullulan and capsule fill formulation comprisingabout 12 mg of the SPRM or a pharmaceutically acceptable salt thereofdispersed in an excipient mixture of (a) about 4% (w/w) isopropylmyristate; (b) about 95.98% (w/) PEG 1000 and (c) about 0.02% BHT. 32.The formulation of claim 23, wherein the capsule comprises about 85 to90 wt % pullulan.
 33. The formulation of claim 31, wherein the capsulecomprises pullulan in an amount of 86.3% by weight, potassium chloridein an amount of 1.32% by weight, carrageenan in an amount of 0.27% byweight, surfactants selected from sugar esters, sorbitan monolaurate andcombinations thereof in an amount of 0.15% by weight and water.
 34. Amethod of treating a progesterone-dependent condition in a subject inneed thereof, the method comprising: administering a mucoadhesivecapsule comprising pullulan and a capsule fill formulation to thevaginal mucosa of the subject, wherein the capsule fill formulationcomprises a SPRM or a pharmaceutically acceptable salt thereof dispersedin an excipient mixture comprising (a) isopropyl myristate or isopropylpalmitate and (b) a polyethylene glycol, wherein the capsule fillformulation produces an increased AUC with vaginal administration ascompared to a capsule fill formulation lacking isopropyl myristate orisopropyl palmitate to the vaginal mucosa of the patient, and whereinthe progesterone-dependent condition is selected from the groupconsisting of endometriosis, adenomyosis, endometriomas of the ovary,dysmenorrhea, uterine fibroids, endometrial hyperproliferation, ovariancancer, and cervical cancer.
 35. The method of claim 34, wherein theprogesterone-dependent condition is endometriosis.
 36. The method ofclaim 34, wherein the progesterone-dependent condition is uterinefibroids.
 37. The method of claim 34, wherein the progesterone-dependentcondition is endometrial hyperproliferation.
 38. The method of claim 34,wherein the isopropyl myristate or isopropyl palmitate is present in anamount ranging from 1% to 15% (w/w) of the excipient mixture andpolyethylene glycol is present in an amount ranging from 99% to 85%(w/w) of the excipient mixture.
 39. The method of claim 34, wherein theisopropyl myristate or isopropyl palmitate is present in an amountranging from 2% to 8% (w/w) of the excipient mixture and polyethyleneglycol is present in an amount ranging from 98% to 92% (w/w) of theexcipient mixture.
 40. The method of claim 34, wherein the isopropylmyristate or isopropyl palmitate is present in an amount ranging from 3%to 5% (w/w) and polyethylene glycol is present in an amount ranging from97% to 95% (w/w) of the excipient mixture.
 41. The method of claim 34,wherein the SPRM or the pharmaceutically acceptable salt thereof ispresent in an amount ranging from 2 to 80 mg.
 42. The method of claim34, wherein the mucoadhesive capsule is administered once per day.